Pharmaceutical Substances Syntheses, Patents, Applications - Part 15 docx

Aspoxicillin
A
141
with
immovable
E.
coli
(ATCC 11303):
Sato,
T.
et al.: Biotechnol. Bioeng. (BIBIAU)
17,
1797 (1975).
US 3 791 926 (Tanabe; 12.2.1974; J prior. 28.10.1971).
US 4 138 292 (Tanabe, 6.2.1979; J-prior. 2.7.1976).
Fusee, M.C. et
a].: Appl. Environ. Microbiol. (AEMIDF) 42,672 (1981).
US 4 436 813 (Purification Engineering; 13.3.1984; appl. 16.3.1982).
US 4 560 653 (Grace; 24.12.1985; appl. 6.6.1983).
EP
110 422 (Tanabe; appl. 2.12.1983; J prior. 3.12.1982).
Fonnulation(s):
many different formulations
Trade Name(s):
D: Eubiol (Chephasaar) F: Megamag (Mayoly- numerous combination
numerous combination Spindler; as magnesium preparations
preparations salt) I: Oral
K
(Sc1avo)-comb.
Sargenon (ASTA Medica; Polase (Wyeth)-comb.
with arginine)

Aspoxicillin
(TA-058)
ATC: JO1
Use: semisynthetic penicillin (for
parenteral administration), derivative
of amoxicillin
RN: 63358-49-6 MF: C21H,N507S MW: 493.54
LD,,: >logkg (M, i.v.)
CN:
[2S-(2a,5a,6~)]-N-methyl-~-asparaginyl-N-(2-carboxy-3,3-dimethyl-7-oxo-4-thia-
1
-
azabicyclo[3.2.0]hept-6-yl)-D-2-(4-hydroxyphenyl)glycinamide
0
NH,
Nps-CI
.
K2CD3.
pH
8
HN/N~s
o-nitrophenyl-
H3C\O~COOH
sulfenyl
chloride
4-methyl
D-ospartate
(1)
hydrochloride
I

H
~
succinimide
~*-meth~l-~?-
142
A
Aspoxicillin
I
OH
amaxicillin
(9.
v.)
0-4-hydrony-
phenylglycine
thiobenzarnide
OH
(111)
CO~H
3.
N~H,
,
N(C2H5),,
-25
OC
Ls
CH,
HzN H
0
H
Aspoxicillin

Aspoxicillin
r-7
2.
isobutyl chloraforrnate
3.
6-arninopenicillanic acid
4.
thiobenzarnide
Reference(s):
Wagatsuma,
M.
et al.:
J.
Antibiot. (JANTAJ)
36,
147 (1983).
US 4 053 609 (Tanabe Seiyaku; ll.lO.1977; UK-prior. 12.9.1975; J-prior. 27.12.1975, 29.12.1975).
GB 1 533 413 (Tanabe Seiyaku; appl. 12.9.1975 and 16.8.1976).
GB 1 533 414 (Tanabe Seiyaku; appl. 3.12.1976; J-prior. 27.12.1975).
DOS 2 638 067 (Tanabe Seiyaku; appl. 24.8.1976; GB-prior. 12.9.1975, 27.12.1975, 29.12.1975).
puri'catinn:
US 4 313 875 (Tanabe Seiyaku; 2.2.1982; J-prior. 11.9.1979).
EP 25 233 (Tanabe Seiyaku; appl. 10.9.1980; J-prior. 11.9.1979).
trihydrate:
US 4 866 170 (Tanabe Seiyaku; 12.9.1989; J-prior. 24.9.1986).
EP 261 823 (Tanabe Seiyaku; appl. 3.9.1987; J-prior. 24.9.1986)
Astemizole
A
143
lyophilized

preparation:
US
4 966 899
(Tanabe Seiyaku;
30.10.1990;
J-prior.
14.1.1987).
Formulation(s):
powder in vial
1
g,
2
g
Trade Name(s):
J: Doyle (Tanabe; 1987)
Astemizole
(R
43512)
ATC:
R06AX11
Use:
antihistaminic, antiallergic
RN:
68844-77-9
MF:
C,,H,,FN,O
MW:
458.58
EINECS:
272-441-9

LD,,:
35
mag
(M,
i.v.);
2560
mglkg
(M,
p.0.);
28.2
mglkg
(R,
i.v.);
>2560
mglkg
(R,
p.0.);
21.8
mglkg (dog,
i.v.);
>320
mglkg (dog, p.0.)
CN:
l-[(4-fluorophenyl)methyl]-N-[I-[2-(4-methoxyphenyl)dhyl]-4-piperidinyl]-1H-benzimidazol-2-amine
H2N
~o~cH3
ethyl 4-ornino-
piperidine-1 -carboxylaie
2-nitro- N,N-diethyl-
1

-isothiocyanato-
aniline thiocarbomoyl 2-nitrobenzene
chloride
4-fluorobenzyl
chloride
0
2-(4-methoxyphenyl)- Asternizole
144
A
Astromicin
Reference (s):
US 4 219 559 (Janssen; 26.8.1980; prior. 10.1.1979).
EP 5 3 18 (Janssen; appl. 30.3.1979; USA-prior. 10.1.1979; 3.4.1978).
synthesis of
1
-isothiocyanato-2-nitrobenzene:
Sayigh, A.A.R.: J. Org. Chem. (JOCEAH) 30,2465 (1965).
synthesis of
N,N-diethylthiocarbamoyl
chloride:
Goerdeler, J.; Luedke, H.: Chem. Ber. (CHBEAM) 103,3393 (1970).
v. Braun: Ber. Dtsch. Chem. Ges. (BDCGAS) 36,2274 (1903).
Billeter: Ber. Dtsch. Chem. Ges. (BDCGAS) 26, 1686 (1893).
Goshorn et al.: Org. Synth. (ORSYAT) 35,55 (1955).
US 2 466 276 (Sharples Chemicals Inc.; 5.4.1949; appl. 2.2.1946).
Formulation(s):
drops 2 mglml; susp. 30 ml (0.2
%);
tabl. 10 mg
Trade Name(s):

D: Hismanal (Janssen-Cilag; GB: Hismanal (Janssen-Cilag; J: Hismanal (Mochida)
1985) 1983) USA: Hismanal (Janssen)
F: Hismanal (Janssen-Cilag; I: Hismanal (Janssen; 1987)
1986) Histamen (Polifarma)
Astromicin
(Fortimicin A)
ATC: JOlG
Use: aminoglycoside antibiotic
RN: 55779-06-1 MF:
C17H3,N506 MW: 405.50
LD,,: 380 mglkg (M, i.v.); 400 mglkg (M, p.0.)
CN:
4-amino-l-[(aminoacetyl)methylamino]-1,4-dideoxy-3-0-(2,6-diamino-2,3,4,6,7-pentadeoxy-~-~-lyxo-
heptopyranosy1)-6-0-methyl-L-chiro-inositol
sulfate
(1:2)
RN: 72275-67-3 MF: C17H35N50h. 2H2O4S MW: 601.65
LD,,:
94mgkg(M,i.v.); 13.6g/kg(M,p.o.);
86 mgkg (R, i.v.); >10 gkg (R, p.0.);
214 mgkg (dog, i.v.)
Astromicin
Preparation by fermentation of
Micromonospora olivoasterospora
FERM-P1560 (identical with
Micromonospora
sp.
MK-70; ATCC 31009 and ATCC 31010) and isolation/purification on ion-exchanger and column
chromatography.
Atenolol

A
145
Reference(s):
Nara,
T.
et al.: J. Antibiot. (JANTAJ) 30, 533 (1977).
Okachi,
R.
et al.: J. Antibiot. (JANTAJ) 30, 541 (1977).
US
3 976 768 (Abbott; 24.8.1976; appl. 22.7.1974; J prior. 23.7.1973).
GB
1 473 356 (Abbott; appl. 22.7.1974; J prior. 23.7.1973).
FR
2 238 502 (Kyowa
Hakko;
appl. 22.7.1974; J prior. 23.7.1973).
DE
2 435 160
structure:
Egan,
R.S. et al.: J. Antibiot. (JANTAJ) 30,552 (1977).
Formulation(s):
amp. 200 mg
Trade Narne(s):
J:
Fortirnicin (Kyowa Hakko;
1985)
Atenolol
ATC: C07AA; C07AB03

Use: antiadrenergic (P-receptor),
antihypertensive
RN:
29122-68-7 MF: CI,H22N203
MW:
266.34 EINECS: 249-451-7
LD,,:
>57 rnglkg
(M,
i.v.);
2 glkg (M, p.0.);
77 rngkg
(R,
i.v.); 2 glkg (R, p.0.)
CN:
4-[2-hydroxy-3-[(1-rnethylethyl)amino]propoxy]benzeneacetamide.
HO
NoCN.NaOH,
DMF.
130
T
2
DL-4-hydroxy-
phenylgiycine
4-hydroxy- 4-hydroxyphenyl
benzyl cyanide acetornide
(I)
@
alternative synthesis of
4-hydroxyphenylacetarnide

arnine
epichloro- 4-(2.3-epoxyprop0xy)-
HO HO
aCOOH
+
H3C-OH
-
aq.
NH,
Atenolol
4-hydroxyphenyl-
acetic acid
hydrin phenylacetamide
146
A
Atorvastatin calcium
Reference(s):
US 3 934 032 (ICI; 20.1.1976; prior. 10.3.1972).
US
3 663 607 (ICI; 16.5.1972; GB-prior. 21.2.1969).
US 3 836 671 (ICI; 17.9.1974; GB-prior. 21.2.1969, 24.9.1969, 18.11.1970 and 19.11.1970).
DOS 2 007 75
1 (ICI; appl. 19.2.1970; GB-prior. 21.2.1969 and 24.9.1969),
GB 1 285 038 (ICI; appl. 21.2.1969; valid from 24.9.1969).
alternative synthesis:
GB 1 391 444 (ICI; appl. 13.7.1971; valid from 19.6.1972).
4-hydroxybenzyl cyanide:
GB 1 522 477 (ICI; appl. 13.8.1974; valid from 11.1
1.1975).
US

4 154 757 (ICI; 15.5.1979; appl. 22.5.1978).
Formulation(s):
amp. 5 mg/lO ml; f. c. tabl. 25 mg, 50 mg, 100 mg
Trade Name(s):
D: Atebeta (betapharm)
duratenol (durachemie)
Falitonsin (ASTA Medica
AWD)
Tenormin (Zeneca; 1976)
Tri-Normin (Zeneca; 1984)
F:
Betatop (EG Labo)
Beta-Adalate (Bayer)-
comb.
Tenordate (Zeneca)-comb.
TCnormine (Zeneca; 1979)
GB: Beta-adalat
(Bayer)-comb.
Kalten (Zeneca)-comb.
Tenben (Galen)-comb.
Tenif (Zeneca)-comb.
Tenoret-50 (Zeneca)-comb.
Tenoretic (Zeneca)-comb.
Tenormin (Zeneca; 1976)
Totamol (CP Pharm.)
J:
Tenormin (ICI-Sumitomo
Chem.; 1984)
USA: Tenoretic (Zeneca; 1984)
Tenormin (Zeneca; 1981)

Atorvastatin calcium
(CI-98
1;
YM-548)
ATC: ClOAA05
Use: hyperlipidemic, HMG-CoA-
reductase inhibitor
RN: 134523-03-8 MF: C,,H,,CaF,N40,,
MW:
1155.36
CN:
[R-(R*,R*)]-2-(4-fluorophenyl)-P,6-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl~-
1H-pyrrole-1-heptanoic acid calcium salt (2:l)
free
acid
RN:
134523-00-5 MF: C,,H3,FN,0, MW: 558.65
(CH3
OH"
"-a;
CH3
F
.HO
~~~7
+
6
-
3%
THF,
N(C2H5)3

b1
a"",
4-fluorabenzaldehyde.
thiozoliurn salt
\
2-isobutyryl- benz- 2-benzylidene-4-
ocetanilide oldehyde rnethyl-3-oxa-N-
phenylpentanornide
Atorvastatin
calcium
A
147
1.
pivalic wid.
toluene
2.
HCI.
CH30H
-
CHO
4-(4-f1uorophenyl)-2- 3-ominopropion.
isabutytyl-3-phenyl- aldehyde
4-0x0-N-phenyl- diethyl ocetol
butyrornide
(I)
5-(4-fluoropheny1)-2-(1-
methylethyl)-1 -(3-0x0-
propyl)-N.4-diphenyl-
1H-pyrrole-3-corbox-
omide (11)

1. MgBr?. THF,
-80
"C
2.
CH3COOH
_______)
(5)-(+)-2-ocetoxy-
1.1
,2-triphenyl-
ethanol
BuLi.
THF
b
v
tert-butyl
.
ocetota
1.
NoOH. THF. CH,OH
2.
HCI
3.
chrornatogrophy
VI
b
148
A
Atorvastatin calcium
1.
NaOH. CH30H, H20

2. CaCI?, H20
Atorvastatin calcium
(R)-(+)-u-
methyl-
benzylamine
1.
separation by HPLC or crystallization
2. NaOH
3. reflux, toluene
VIII
b
Atorvostatin
H3C CH,
X
2.
NaCN
(X).
OMS0
H
C
Cti,
X
CHO
O
O
CH
O
O O
-
H&~0x,,,+131313

,,,,
CN
H3C~O%,~~+'u~'%/0H
1.
p-chlorophenyl-
H3C sulfonyl chlaride
H3C
tert-butyl (4R,6S)-2- tert-butyl (4R.6R)-2-
(6-hydraxyrnethyC2.2-
(6-cyonomethyl-2.2-dimethyl-
dimethyl-1 -3-diaxan- 1.3-dioxan-4-yl)acetate
(XI)
4-yl)acetate
I
Atorvastatin calcium
A
149
Hz, 50 psi, sponge
Ni
H C
CH,
XI
-
X
CHO
O
O
H3C~O~~~"'u"I/\N
H2
H3C

tert-butyl (4R.6R)-2-
[6-(2-ominoethy1)-2.2-
dimethyl-1,3-dioxon-4-
yllocetate (XI)
1.
pivolic ocid, toluene
2. HCI. CH30H, H20
xU+I
-,
YI
+
@
olternotive synthesis of interrnediote
XI:
ethyl 3(R)-hydroxy-
4-cyonobutyrote
(XII1)
tert-butyl 5(R)-hydroxy-
6-cyono-3-oxohexonoote
(XW)
1.
B(C2H5)3. NoBH,. -65 OC
H C CH3
2.
X
? ?
H3C CH3
XIV
,
xl

1.
triethylborone
2. ocetone dirnethyl acetol
@
synthesis of the starting moterial
XII:
ethyl 4-bromo-3(S)-
hydroxybutonoote
@
olternotive synthesis of intermediote
n:
n
OyO
n
ocetonitrile
+
____,
NH2
2-(1,3-dioxolon- ethyl 2-bromo-
2-yl)ethylomine 2-(4-fluorophenyl)
ocetote
ethyl 2-[2-(1.3-dioxolon-
2-yl)ethylamino]-2-(4-
fluorophenyl)ocetote (XV)
isobutyryl
chloride
150
A Atracurium besilate
N,3-diphenyl-
propynomide

1 -[2-(1,3-dioxolan-2-
yl)ethyl]-5-(4-fluoro-
phenyl)-2-(1 -methyl-
ethyl)-N,4-diphenyl-
1 H-pyrrole-3-corb-
oxamide
Reference(s):
a,b
US 4 681 893 (Warner-Lambert; appl. 21.7.1987; USA-prior. 30.5.1986).
EP 409 281 (Warner-Lambert; appl. 23.1 .I991
;
USA-prior. 21.7.1989, 26.2.1991).
EP 680 320
(
Warner-Lambert; appl. 8.1 1.1995; USA-prior. 19.1.1993).
c
Naeminga, T. et al.: Tetrahedron Lett. (TELEAY) 33, 2279-2282 (1992).
WO 9 703 960 (Warner-Lambert; appl. 6.2.1997; USA-prior. 17.7.1995).
ca
Baumann, K.L. et al.: Tetrahedron Lett. (TELEAY) 33, 2283-2284 (1992).
cb
Isbell, H. et a].: Carbohydr. Res. (CRBRAT) 72,301-304 (1972).
d
Roth, B.D. et al.: J. Med. Chem. (JMCMAR) 34,357-366 (1991).
preparation of
N,3-diphenylpropynamide:
Gadwhal, S. et al.: Indian
J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. (IJSBDB) 37B (8), 725-727
(1998).

preparation of intermediates:
WO 9 932 434 (Warner-Lambert; appl. 2.12.1998; USA-prior. 19.12.1997).
WO 9 957 109 (Kaneka Corp.; appl. 28.4.1999; J-prior. 30.4.1998).
WO 9 804 543 (Warner-Lambert; appl. 1.7.1997; USA-prior. 29.7.1996).
US 5 155 25 1 (Warner-Lambert; appl. 13.10.1992; 11.10.199 1).
US 5 103 024 (Warner-Lambert; prior. 17.10.1990).
new crystalline forms of
atorvastatin:
WO 9 703 959 (Warner-Lambert; appl. 8.7.1996; USA-prior. 17.7.1995).
WO 9 703 958 (Warner-Lambert; appl. 6.2.1997; USA-prior. 17.7.1995).
stable oral formulation:
WO 9 416 693 (Warner-Lambert; appl. 4.8.1994; USA-prior. 19.1.1993).
Formulation(s):
tabl. 10 mg, 20 mg, 40 mg
Trade Name(s):
D: Sotis (Parke Davis1 J: Lipitor (Warner-Lambert) Xavator (Parke Davis)
Godecke; Mack, Illert.) Torvast (Pfizer) USA: Lipitor (Parke Davis;
GB: Lipitor (Parke Davis) Tozalip (Guidotti) Pfizer)
Atracurium besilate
ATC: M03AC04
Use: skeletal muscle relaxant
RN: 64228-81-5 MF:
C53H,2N20,,
. 2C6HsO3S MW: 1243.50 EINECS: 264-743-4
CN:
2,2'-[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-
tetrahydro-6,7-dimethoxy-2-methylisoquinolinium]
dibenzenesulfonate